Avanafil is a drug for the treatment of male erectile dysfunction developed by US Vivus Pharmaceutical as authorized by Japan Mitsubishi Tanabe Pharma Corporation. Avanafil is an oral highly-selective phosphodiesterase-5 (PDE-5) inhibitor, which can inhibit the in vivo metabolism of cyclic guanosine monophosphate (CGMP), to strengthen the relaxant effect of smooth muscles and increase the blood flow to the penis, to help erection. Avanafil is approved to appear on the markets by US FDA on Apr. 27, 2012, with the trade name Stendra.
The chemical name of Avanafil (Avanafil, I) is (S)-4-[(3-chloro-4-methoxybenzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidyl methyl)-5-pyrimidinecarboxamide.

The global patent No. WO0183460 and No.WO0119802 for original research of Tanabe Seiyaku reported the preparation method of avanafil and its analogs. According to the method, the avanafil (I) is prepared by the reactions between pyrimidine ring nucleus (X) and the C-2, C-4 and C-5 side chain S-hydroxymethyl pyrrolidine (II), 3-chloro-4-methoxy-benzylamine (VIII) and 2-pyrimidinemethanamine (IX), respectively.

Specifically, the cyclization between methyl thiourea (XI) and diethyl ethoxymethylene (XII) occurs to get pyrimidine ring nucleus 4-hydroxy-2-(methylthio) pyrimidine-5-carboxylate (X); the pyrimidine ring nucleus intermediate (X) is chloridized by phosphorus oxychloride to get 4-chloro-2-methylthio-pyrimidine-5-carboxylate (XIII); the intermediate (XIII) and side chains (VIII) have a substitution reaction to get 4-(3-chloro-4-methoxy-benzylamine)-2-methylthio-pyrimidine-5-carboxylate (IXV); then the intermediate (IXV) is oxidized by peroxybenzoic acid to get 4-(3-chloro-4-methoxy-benzylamino)-2-methylthio-pyrimidine oxidized with peracetic acid-5-carboxylate (XV); then the intermediate (XV) and the side chains (II) have a nucleophilic addition reaction to produce 4-[(3-chloro-4-methoxybenzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine-5-carboxylate (XVI); finally the intermediate (XVI) is hydrolyzed and has a acylation reaction with the side chain (IX) to get avanafil (I).

The above patent of original research also discloses a method for preparing analogues using 2,4-dichloropyrimidine as a raw material. Under the action of N-butyllithium and diisopropylamine, carbanion forms by 2,4-dichloropyrimidine; under the ultra-low temperature-78° C., it has a nucleophilic addition reaction with carbon dioxide or other carbonyl compounds, to form 5-substituted-2,4-dichloropyrimidine derivative (XVII). The derivative (XVII) reacts with C-2, C-4 and C-5 side chain to prepare the phosphodiesterase-5 (PDE-5) inhibitor with the structure similar to the target compound (I).
Analogs of the Target Compound
As shown from above, regardless of using methylthio-substituted pyrimidine or dichloropyrimidine as the staring material, the raw materials used in the preparation process are not readily available, and there are many defects such as many synthesis steps, complex process and difficulty of separation, etc. especially the ultra-low temperature conditions, high-pressure conditions for carbonylation of carbon dioxide and the anhydrous anaerobic conditions for the multi-step reactions of metal reagents, it is difficult to achieve industrialization for the whole synthetic route.